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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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Poly(ADP-ribose) polymerase-1 down-regulates BRCA2 expression through the BRCA2 promoter

Jinhua Wang1, Chunjing Bian, Jing Li

  • 1Institute of Basic Medical Sciences and School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China.

The Journal of Biological Chemistry
|November 8, 2008
PubMed

Insights

Poly-(ADP-ribose) polymerase-1 (Parp-1) represses BRCA2 tumor suppressor gene expression by binding to its promoter. Inhibiting Parp-1 activity increases BRCA2 levels, crucial for DNA repair and genomic stability.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • BRCA2 is a critical tumor suppressor involved in DNA repair and genomic stability.
  • Previous studies identified activators and a repressor of BRCA2 promoter activity, along with an inhibitory 67-bp region.
  • The precise mechanism by which this 67-bp region regulates BRCA2 expression remained unclear.

Purpose of the Study:

  • To identify the protein that binds to the silencer-binding region within the 67-bp repression region of the BRCA2 promoter.
  • To elucidate the role of this protein in regulating BRCA2 expression.

Main Methods:

  • Affinity purification and mass spectrometry to identify the binding protein.
  • Gel shift, antibody super-shift, and chromatin immunoprecipitation (ChIP) assays to confirm in vitro and in vivo binding.
  • Use of Parp-1 inhibitors and siRNA to assess the effect on BRCA2 expression and histone acetylation.

Main Results:

  • Poly-(ADP-ribose) polymerase-1 (Parp-1) was identified as the 120-kDa protein binding to the BRCA2 promoter's repression region.
  • Parp-1 was confirmed to associate with the BRCA2 promoter both in vitro and in vivo.
  • Inhibition of Parp-1 activity or gene expression led to increased endogenous BRCA2 levels.
  • Parp-1 inhibition reduced histone H3 lysine 9 acetylation and blocked Parp-1 binding to the promoter.

Conclusions:

  • Parp-1 acts as a repressor of BRCA2 expression.
  • Parp-1 down-regulates BRCA2 by interacting with a specific repression region on its promoter.
  • Targeting Parp-1 may represent a therapeutic strategy to enhance BRCA2 function in DNA repair and maintain genomic integrity.

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